Maria Katselou

AH-7921: the list of new psychoactive opioids is expanded

AH-7921 is a structurally unique synthetic opioid analgesic that has recently entered the drug arena in Europe, the USA, and Japan. Although it was synthesized and patented in the mid-1970s, it was first identified in a seized sample purchased via the Internet in July 2012 and formally brought to the attention of the European Union early warning system in August 2012 by the United Kingdom. Several in vitro experiments and animal model studies established the morphine-like analgesic action of AH-7921 as a μ-opioid receptor agonist that has been found to be several times more potent than codeine and at least as potent as morphine. This novel psychoactive substance has already led to eight non-fatal intoxications and 16 deaths in Sweden, the United Kingdom, Norway, and the USA. Thus, AH-7921 is a current public health risk, and better international collaboration, effective legislation and continuous community alertness are needed to tackle this current growing problem. The aim of this review is to summarize the current knowledge about this drug concerning its chemistry, pharmacology, and toxicology, as well as its international legal status. The limited existing analytical methodologies for the determination of AH-7921 in biological samples are also presented. Published or reported AH-7921-related cases, fatalities, or intoxications, and self reports from drug users are reviewed.

Novel benzoxazine and benzothiazine derivatives as multifunctional antihyperlipidemic agents.

Atherosclerosis is a multifactorial disease with several mechanisms participating in its manifestation. To address this disorder, we applied a strategy involving the design of a single chemical compound able to simultaneously modulate more than one target. We hereby present the development of novel benzoxazine and benzothiazine derivatives that significantly inhibit in vitro microsomal lipid peroxidation and LDL oxidation as well as squalene synthase activity (IC(50) of 5-16 μM). Further, these compounds show antidyslipidemic and antioxidant properties in vivo, decreasing total cholesterol, LDL, triglyceride, and MDA levels of hyperlipidemic rats by 26-74%. Finally, by determination of their in vivo concentration (up to 24 h) in target tissues (blood/liver), it is shown that compounds reach their targets in the low micromolar range. The new compounds seem to be interesting multifunctional molecules for the development of a new pharmacophore for disease-modifying agents useful in the treatment of atherosclerosis.

U-47700. An old opioid becomes a recent danger

U-47700 is a synthetic opioid analgesic and a potent, short acting structural isomer of the earlier opioid AH-7921 that has recently invaded the drug arena in Europe and the Unites States. Although the drug was synthesized and patented in the 1970s, it was first identified in October 2014, as a powder sample that was seized by Swedish Customs. Sweden formally notified the European Union Early Warning System in January 2015. Animal studies proved that U-47700 is a strong μ-opioid receptor agonist and has a morphine-like analgesic action, being 7.5 times higher than morphine. The drug has a much lower affinity for the κ-opioid receptor. This newly appearing psychoactive substance has already led to more than 25 confirmed fatalities associated with U-47700 in Europe and the United States and to six non-fatal intoxications reported in the United States. The aim of this review is to summarize the current knowledge about this drug, regarding its chemistry, synthesis, pharmacology, toxicology and metabolism, as well as its international legal status. The existing analytical methods for the determination of U-47700 in biological samples are also presented. Published or reported U-47700 related cases, fatalities or intoxications, and self reports from drug users are reviewed.

Metabolites replace the parent drug in the drug arena. The cases of fonazepam and nifoxipam

Fonazepam (desmethylflunitrazepam) and nifoxipam (3-hydroxy-desmethylflunitrazepam) are benzodiazepine derivatives and active metabolites of flunitrazepam. They recently invaded the drug arena as substances of abuse and alerted the forensic community after being seized in powder and tablet forms in Europe between 2014 and 2016. A review of all the existing knowledge of fonazepam and nifoxipam is reported, concerning their chemistry, synthesis, pharmacology and toxicology, prevalence/use, biotransformation and their analysis in biological samples. To our knowledge, fonazepam and nifoxipam-related intoxications, lethal or not, have not been reported in the scientific literature. All the available information was gathered through a detailed search of PubMed and the World Wide Web.

Bioanalysis of antihistamines for clinical or forensic purposes

Antihistamines are a class of drugs that inhibit the action of histamine and are used to alleviate symptoms associated with allergic reactions, but some of them can cause side effects, the most unpleasant and dangerous of which are the sedative effects that may hinder important psychological functions and impair skilled performance. These side effects could decrease safety in certain common and critical tasks, such as driving or operating machinery, leading to accidents. Antihistamines can also cause intoxications, sometimes lethal, especially when co-administered with alcohol or other sedative drugs. Thus, the development of analytical methods for their determination in biological fluids is considered to be useful for the investigation of clinical and forensic cases. These methodologies could also be used for pharmacokinetic studies. Several liquid and a few gas chromatographic methods have been developed for the determination of antihistamines in biological matrices after proper pretreatment procedures. This article reviews the published analytical methodologies that were gathered through the search in PubMed database and the recent developments on isolation or determination of antihistamines in biological materials. Current trends and future perspectives on bioanalysis of antihistamines are also discussed. Copyright

Development and validation of a GC–MS method for the determination of hydroxyzine and its active metabolite, cetirizine, in whole blood

HighlightsA GC–MS method was developed and validated for the simultaneous determination of hydroxyzine and its active metabolite, cetirizine, in whole blood.The developed method provided significant advantages regarding sensitivity and linear dynamic range of related, previously published, methods.The method can be used during the investigation of clinical and forensic toxicology cases.The developed method was successfully applied during the investigation of clinical cases where these antihistamines were detected.The method could also be applied to pharmacokinetic studies concerning these antihistamines and the determination of more antihistamines in blood after proper optimization and validation. Abstract A simple, rapid, sensitive and accurate gas chromatography–mass spectrometric method was developed and validated for the simultaneous determination of hydroxyzine and cetirizine in whole blood. Solid‐phase extraction procedure using Bond Elut LRC Certify II columns was used for the isolation of hydroxyzine and cetirizine from 1 mL whole blood followed by derivatization with a mixture of acetic anhydride:n‐propanol (1:1, v/v). Limits of detection and quantification were 1.50 and 5.00 ng/mL, respectively. The assay was linear within the concentration range of 5.00–1000.0 ng/mL and the correlation coefficient was R2 ≥ 0.993 for both analytes. Absolute recovery was determined at three quality control concentration levels and was found to be at least 87.2% for both substances. Intra‐day and inter‐day accuracy values for both hydroxyzine and cetirizine were ranged from −1.2 to 3.8% and −2.7 to 2.0%, respectively, at the three concentration levels studied, whereas their respective intra‐day and inter‐day precision values were less than 9.9 and 6.5%, respectively, in terms of relative standard deviation (%RSD). The developed method was successfully applied for the quantification of hydroxyzine and cetirizine concentrations in whole blood, during the investigation of clinical cases where these two antihistamines were detected.

Furanylfentanyl: another fentanyl analogue, another hazard for public health

The fentanyls are a family of drugs that have caused hundreds of deaths in Europe and the United States. They first appeared in the United States in the late 1970s; they were sold as heroin to unsuspecting users. Furanylfentanyl is a potent synthetic drug, an analogue of fentanyl that belongs to the above family. It has no proven medical use, but it is abused throughout the world for its opioid-like effects. The drug is mainly manufactured in China and is distributed worldwide. It is used mainly intranasally, but other routes of administration have also been reported. Furanylfentanyl has been involved in many intoxication cases, fatal or not, and many seizures of the drug have been recorded. The aim of this review is to summarize all the available information on furanylfentanyl, concerning its chemistry, synthesis, prevalence, metabolism, pharmacology, and toxicology, as well as its legal status. Analytical methods for the determination of furanylfentanyl in biological specimens are presented. Intoxications and lethal cases published in the scientific literature or reported on the web are also reviewed.

“Poor man’s methadone” can kill the poor man. Extra-medical uses of loperamide: a review

Loperamide is a phenylpiperidine derivative and an opioid agonist that was launched by Janssen Pharmaceutica in 1973. It was initially classified in the United States as a Schedule II drug and was transferred to Schedule V in 1977; it has not been listed as a controlled substance since 1982. Loperamide is used for the symptomatic treatment of diarrhea and gastrointestinal inflammation. It has a low potential for central nervous system effects when administered in therapeutic doses. However, when used in supratherapeutic doses, either for self-treatment or drug abuse (opioid substitute), it can lead to life-threatening cardiac effects. The US Food and Drug Administration and the global community are concerned about these severe side effects, suggesting the need for control worldwide. This article reviews the existing knowledge on loperamide, including its chemistry, synthesis, pharmacology, toxicology, pharmacokinetics, biotransformation, its medicinal use, dependence potential, abuse of the drug, reported intoxications, fatalities, its determinations in biological samples, and its current legal status. All available information was gathered through a detailed search of PubMed and the World Wide Web.

Developing potential agents against atherosclerosis: Design, synthesis and pharmacological evaluation of novel dual inhibitors of oxidative stress and Squalene Synthase activity

For the treatment of multifactorial and complex diseases, it has become increasingly apparent that compounds acting at multiple targets often deliver superior efficacy compared to compounds with high specificity for only a single target. Based on previous studies demonstrating the important antioxidant and anti-hyperlipidemic effect of morpholine and 1,4-benzo(x/thi)azine derivatives (A-E), we hereby present the design, synthesis and pharmacological evaluation of novel dual-acting molecules as a therapeutic approach for atherosclerosis. Analogues 1-10 were rationally designed through structural modifications of their parent compounds (A-E) in order for structure-activity relationship studies to be carried out. Most compounds showed a significant inhibition against Squalene Synthase activity exhibiting at the same time a very potent multimodal antioxidant (against lipid peroxidation and as free-radical scavengers) effect, thus bringing to light the 2-aryl-1,4-benzo(x/thia)zin-2-ol scaffold as an outstanding pharmacophore for the design of potent antioxidants. Finally, the replacement of the octahydro-1,4-benzoxazine moiety of lead compound D with its respective 1,4-benzothiazine (compound 4), although conserved (anti-hypercholesterolemic) or even improved (anti-hyperlipidemic) activity, did not preserve the anti-diabetic effect of D.

Diphenidine: a dissociative NPS makes an entrance on the drug scene

PurposeDiphenidine is a potent synthetic dissociative anesthetic drug that has recently emerged in drug markets of Europe, Japan and America. The aim of this review is to summarize the current knowledge about this drug concerning its chemistry, synthesis, prevalence, pharmacology, toxicology and metabolism, as well as its legal status. Analytical methodologies developed for the determination of diphenidine in biological specimens and published diphenidine-related intoxications, fatal or not, are also presented.MethodsAll the reviewed information was gathered through a detailed search of PubMed and the World Wide Web using proper keywords.ResultsDiphenidine is not approved for medical or veterinary use, but it is used illicitly around the world for recreational purposes or as a substitute of other controlled dissociative drugs. It is available through the Internet in powder form for oral administration, smoking or vaporization. Since its first appearance in the drug market in 2013, seizures have been reported worldwide and its abuse has already caused intoxications and deaths in Europe and Japan, thus leading to its scheduling in the United Kingdom and Canada during the second semester of 2016.ConclusionsDiphenidine is a harmful dissociative drug that recently gained serious concern for public health. International and local authorities should take all the appropriate actions and measures to avoid the expansion of this new threat.